Enantioselective synthesis of fluorene derivatives by chiral phosphoric acid catalyzed tandem double friedel-crafts reaction

Article abstract of DOI:10.1002/chem.200901369

A tandem double Friedel Crafts reaction of indoles with 2-formylbiphenyls, leading to 9-(3-indolyl) fluorene derivatives with up to 96% ee was reported. Several solvents, namely, benzene, dichioromethane, and carbon tetrachloride, were screened and the us

Full text of DOI:10.1002/chem.200901369

COMMUNICATION
DOI: 10.1002/chem.200901369
Enantioselective Synthesis of Fluorene Derivatives by Chiral Phosphoric
Acid Catalyzed Tandem Double Friedel–Crafts Reaction
Feng-Lai Sun, Mi Zeng, Qing Gu, and Shu-Li You*[a]
The asymmetric Friedel–Crafts reaction is one of the most
powerful methods to synthesize optically active aromatic
compounds,[1] and chiral Brønsted acids have recently
emerged as efficient catalysts.[2] Chiral phosphoric acids, first
introduced by Akiyama et al. and Terada and Uraguchi as
organocatalysts,[3] were shown to be effective in the Friedel–
Crafts alkylation reactions of indoles and pyrroles by several
groups. However, electrophilic partners that can be activat-
ed by chiral phosphoric acids in Friedel–Crafts reactions
have, so far, been limited to imines,[4] enamides,[5] a,b-unsa-
turated carbonyls,[6] and nitroolefins.[7] Developing new, suit-
able electrophilic partners and novel catalytic models for
chiral phosphoric acid catalyzed reactions are extremely de-
sirable. In this regard, vinyl ether[8] and nitroso compounds[9]
Scheme 1. Chiral phosphoric acid catalyzed tandem double Friedel–
Crafts reaction.
have recently been developed successfully.[10] Alcohols are
among the most abundant chemicals and synthetic inter-
mediates, however, their use in enantioselective Friedel–
Crafts reactions has only appeared recently.[11] To the best of
our knowledge, the only example involving the use of alco-
hols in the Brønsted acid catalyzed asymmetric Friedel–
Crafts reaction was carried out by Rueping et al., in which
chiral N-triflylphosphoramide was used and a moderate en-
antiomeric excess (ee) value was obtained.[6a]
synthesis,[14] this represents the first asymmetric synthesis of
fluorene derivatives. More interestingly, the current reaction
proceeds with the activation of both carbonyl and hydroxy
groups by a chiral phosphoric acid. The enantiocontrol is
likely to be made possible through the close proximity of
the chiral phosphate counterion to the 3-benzylidene-3H-in-
dolium ion.[15] Herein, we report a tandem double Friedel–
Crafts reaction of indoles with 2-formylbiphenyls, leading to
9-(3-indolyl)fluorene derivatives with up to 96% ee.
We first examined the reaction between 3’,5’-dimethoxybi-
phenyl-2-carbaldehyde (2a) and 2-methyl indole (3a) cata-
lyzed by different, readily available, chiral phosphoric
acids.[16] To our delight, reaction of 2a and 3a in the pres-
ence of (S)-1 (5 mol%) and 5 ꢀ molecular sieves (MS), in
toluene at room temperature, proceeded smoothly to afford
fluorene 4aa in 70% yield with 75% ee (Table 1, entry 1).
Optimization of the reaction conditions was carried out and
the results are summarized in Table 1. Lowering the temper-
ature to 08C resulted in an increase of enantioselectivity
(81% ee; Table 1, entry 2). Several solvents, namely, ben-
zene, dichloromethane, and carbon tetrachloride, were
screened and the use of carbon tetrachloride resulted in an
excellent 92% ee (Table 1, entries 2–5). Further screening of
During our recent study on the chiral Brønsted acid cata-
lyzed Friedel–Crafts reaction, we found that a chiral phos-
phoric acid could catalyze the Friedel–Crafts reaction of
indole with 2-formylbiphenyl derivatives. Interestingly, this
reaction proceeded through a double Friedel–Crafts alkyla-
tion process,[12] providing the 9-(3-indolyl)fluorene deriva-
tives with high ee values (Scheme 1).[13] To the best of our
knowledge, despite their significant applications in organic
[a] Dr. F.-L. Sun, M. Zeng, Dr. Q. Gu, Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, 345 Lingling Lu
Shanghai 200032 (China)
Fax : (+86)21-5492-5087
E-mail: slyou@mail.sioc.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901369.
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Table 1. Screen of the reaction conditions.
Table 2. Substrate scope of indoles in the tandem double Friedel–Crafts
reaction.
Entry[a]
R1
R2
t
Product
Yield [%][b]
ee [%]
Entry[a] Solvent
Additive T [8C]
t
Yield [%][b] ee [%]
1
2
3
4
5
6
7
Me
Me
Me
Me
Me
Me
Me
H
H
20 min
30 min
30 min
20 min
30 min
30 min
70 min
3 h
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
92
90
94
96
91
66
84
37
85
86
96
91
93
93
77
90
81[c]
89
89
73
5-Me
5-Br
5-Cl
5-F
5-CH3O
7-Br
H
1
2
3
4
5
6
7
8
9
toluene
toluene
benzene 5 ꢀ
CH2Cl2
CCl4
CCl4
CCl4
CCl4
CCl4
5 ꢀ
5 ꢀ
20
0
30 min 70
30 min 66
10 min 85
75
81
80
85
92
96
90
88
83
0
5 ꢀ
5 ꢀ
5 ꢀ
4 ꢀ
3 ꢀ
–
0
0
ꢀ15
ꢀ15
ꢀ15
ꢀ15
4 h
95
10 min 90
20 min 90
3 h
30 min 51
40 min 50
8[d]
9
10
85
Et
Ph
H
H
30 min
24 h
4aj
[a] Reaction conditions: 2a (0.2 mmol), (S)-1 (5 mol%), 3 (0.3 mmol),
and 5 ꢀ molecular sieves (150 mg) in CCl4 (3 mL) at ꢀ158C. [b] Yield of
the isolated product. [c] An X-ray structure of the enantiopure N-Boc de-
rivative of 4ag disclosed the S configuration. [d] The reaction was carried
out at room temperature.
[a] Reaction conditions: 2a (0.1 mmol), (S)-1 (5 mol%), 3a (0.15 mmol),
and molecular sieves (70 mg) in 2 mL of solvent. [b] Yield of the isolated
product.
the reaction temperature led to 96% ee at ꢀ158C (Table 1,
entry 6). Replacement of the 5 ꢀ MS with 4 or 3 ꢀ MS led
to a slight decrease of the enantioselectivity. In general, the
presence of molecular sieves increases the enantioselectivity
because water is generated during the second Friedel–Crafts
reaction with the hydroxy group (Table 1, entries 6–9).
Various indoles were treated with 2-formylbiphenyl 2a
under the optimized reaction conditions ((S)-1 (5 mol%)
with 5 ꢀ MS in CCl4 at ꢀ158C). The results are summarized
in Table 2.
For the 2-methylindole derivatives, different substituents,
such as 5-Me, 5-Br, 5-Cl, 5-F, 5-OMe, and 7-Br, were all tol-
erated to afford the fluorene products with good to excellent
yields (66–96%). Enantioselectivities of over 90% ee were
obtained for most of the substrates except those with 5-F
(77% ee) and 7-Br (81% ee) (Table 2, entries 2–7). Protec-
tion of the indole NH of the bromo-containing compound
4ag by treatment with Boc2O led to the formation of 5 with-
out loss of optical purity. An X-ray structure of enantiopure
5 was obtained, which enabled the absolute configuration of
the product to be assigned as S (Figure 1).[17]
Indoles with different substituents at the 2-position were
also examined. Excellent ee values were obtained for indole
(89%) and 2-ethylindole (89%), however, the use of indole
resulted in a relatively low yield due to the formation of a
bisalkylated byproduct (Table 2, entries 8–9). The reaction
also tolerated 2-phenylindole as a substrate, giving the de-
sired product in 86% yield with 73% ee (Table 2, entry 10).
The substrate scope of the reaction was further explored
by subjecting various 2-formylbiphenyls to the optimized re-
action conditions with 2-methyl indole (3a) (Scheme 2). The
desired fluorene derivatives were formed in good to excel-
Figure 1. X-ray structure of enantiopure (S)-5. Ellipsoids at 30% proba-
bility.
lent yields and with excellent ee values (92–96%) except for
the fluorene 4da, which was formed with 74% ee.
The reaction mechanism proposed is depicted in
Scheme 3. The first Friedel–Crafts reaction between 2a and
3a is catalyzed by phosphoric acid to afford the secondary
alcohol I. Intermediate I is unstable under the reaction con-
ditions and attempts to isolate this alcohol from the reaction
mixture have, so far, been unsuccessful. The exposure of al-
cohol I to the chiral phosphoric acid leads to the formation
of the close counterion II, in which the chiral phosphate
anion creates a chiral environment to control the enantiose-
lectivity of the second Friedel–Crafts reaction. Interestingly,
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Enantioselective Synthesis of Fluorene Derivatives
COMMUNICATION
Scheme 4. Friedel–Crafts reaction of bisindole 6 and N-methylindole.
with 2-formylbiphenyl derivatives, affording the fluorene de-
rivatives with up to 96% ee. This represents the first enan-
tioselective synthesis of fluorene derivatives. In addition, the
activation of both carbonyl and hydroxy groups by chiral
phosphoric acid and the high enantiocontrol through the
close proximity of the chiral phosphate counterion to the 3-
benzylidene-3H-indolium ion provides a new reaction model
for chiral phosphoric acid catalysis. Ongoing efforts in our
laboratory focus on mechanistic study and further applica-
tion of this novel catalytic model.
Scheme 2. Substrate scope of the 2-formylbiphenyl partner for the
tandem double Friedel–Crafts reaction.
Experimental Section
General procedure for the catalytic asymmetric Friedel–Crafts reaction:
In a dry Schlenk tube, biphenyl-2-carbaldehyde 2 (0.20 mmol), 5 ꢀ mo-
lecular sieves (150 mg), and phosphoric acid (S)-1 (6.0 mg, 0.01 mmol)
were dissolved in CCl4 (1.5 mL) at ꢀ158C under argon. The solution was
stirred for 5 min, then substituted indole 3 (0.3 mmol) in CCl4 (1.5 mL)
was added slowly for 15 min at ꢀ158C. After the reaction was complete
(monitored by TLC), saturated aqueous NaHCO3 (1 mL) was added to
quench the reaction. The mixture was extracted with CH2Cl2 (10 mL).
The organic layer was separated and dried over anhydrous Na2SO4. The
solvents were removed under reduced pressure and the residue was puri-
fied by flash chromatography (ethyl acetate/petroleum ether 1:10!1:5)
to afford the product.
Scheme 3. Reaction pathways for the tandem double Friedel–Crafts reac-
tion of 2a with 3a.
since bisindole 6 can be observed during the reaction, an al-
ternative pathway involving the transformation of 6 to the
intermediate II is included in the catalytic cycle. As evi-
dence for the two coexistent pathways, when bisindole 6 was
isolated and subjected to the optimized reaction conditions,
product 4aa was isolated in 50% yield with 83% ee
(Scheme 4a). In addition, when the N-methyl-2-methylin-
dole was used, the product was obtained in 35% ee
(Scheme 4b). The dramatic decrease of both the ee value
and the reaction time (1 h), compared with those of 2-meth-
ylindole, indicates that the reaction might proceed preferen-
tially through intermediate II, in which the enantiocontrol is
realized through a 3-benzylidene-3H-indolium intermediate.
In summary, we have developed a chiral phosphoric acid
catalyzed tandem double Friedel–Crafts reaction of indoles
Acknowledgements
We thank the National Natural Science Foundation of China (20732006,
20821002), National Basic Research Program of China (973 Program
2009CB825300), and the Science and Technology Commission of Shang-
hai Municipality (07pj14106, 07JC14063) for generous financial support.
We also thank Professor Kuiling Ding and Jiang Wu for helpful discus-
sions.
Keywords: asymmetric catalysis · chiral Brønsted acids ·
fluorenes · Friedel–Crafts reaction · organocatalysis
Chem. Eur. J. 2009, 15, 8709 – 8712
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Received: May 22, 2009
Published online: July 30, 2009
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